CN109475726B

CN109475726B - Microneedle array assembly, drug delivery device and method for large area low pressure infusion of liquid

Info

Publication number: CN109475726B
Application number: CN201780026208.2A
Authority: CN
Inventors: A·T·贝克; R·F·罗斯; E·D·加斯比; L·哈根
Original assignee: Sorrento Therapeutics Inc
Current assignee: Sorrento Therapeutics Inc
Priority date: 2016-04-29
Filing date: 2017-04-17
Publication date: 2021-05-18
Anticipated expiration: 2037-04-17
Also published as: EP3851153A1; KR20220136486A; PL3851153T3; HUE060307T2; EP3851153B1; AU2022202361A1; US20190143090A1; CN113198101B; WO2017189258A2; WO2017189258A3; EP3448493B1; KR20180131629A; AU2017258749B2; CN113198101A; US20220040465A1; JP7068189B2; ES2929477T3; DK3851153T3; US11179554B2; EP3448493A2

Abstract

The uniformity control membrane can be firmly bonded to the upstream side of the microneedle array and is configured such that the resistance to flow through the uniformity control membrane is significantly greater than the resistance to flow through the microneedle array. These differences in flow resistance may facilitate uniform infusion of the liquid formulation into a patient's skin over a large area at relatively low pressure, eg, by capillary action. The large area infusion of the liquid formulation onto the patient's skin is due to the fact that the liquid formulation can be infused through at least a majority of the microneedles in the microneedle array.

Description

Microneedle array assembly, drug delivery device and method for large area low pressure infusion of liquids

Technical Field

The present invention relates generally to devices for delivering liquid formulations into the skin of a patient. In particular, the present disclosure relates to devices having microneedle arrays for transdermal delivery of liquid formulations.

Background

A number of devices utilizing microneedle arrays have previously been developed for transdermal delivery of fluid drugs and other drug compounds. For example, microneedles have the advantage of causing less pain to the patient than larger conventional needles. Furthermore, the traditional way of delivering fluid drugs subcutaneously (usually intramuscularly) through a conventional needle is to deliver large amounts of fluid drugs simultaneously, often resulting in peaks in drug bioavailability. For drugs with certain metabolic profiles, this is not a significant problem. However, many drugs benefit from steady state concentrations in the blood of a patient; a well-known example of such a drug is insulin.

In some cases, transdermal drug delivery devices including microneedle arrays are intended to deliver a liquid formulation at a substantially constant rate over a large area for an extended period of time. In some cases, such microneedle arrays may also require that the liquid formulation be expelled under relatively low pressure in order to infuse the liquid formulation by capillary action. However, there are interference factors associated with the flow through the microneedle array such that the flow may be associated with too few microneedles of the microneedle array.

Disclosure of Invention

One aspect herein is to provide a drug delivery device that includes a microneedle array assembly that is adapted in a manner that seeks to infuse a liquid formulation uniformly into the skin of a patient over a large area at a relatively low pressure. The device can infuse a liquid formulation into the skin of a patient over a large area at a substantially constant rate over an extended period of time, wherein administration of the liquid formulation to the skin of the patient can occur at a relatively low pressure, for example by capillary action.

For example, the microneedle array assembly may include at least one uniform control film securely attached to the upstream side of the microneedle array, and optionally, an additional film may cover the downstream side of the microneedle array. The uniformity control film may be a track etched film or the like, and the uniformity control film and the microneedle array may be cooperatively configured such that the resistance to flow through the uniformity control film is substantially greater than the resistance to flow through the microneedle array. These differences in flow resistance attempt to facilitate, for example, a large area of uniform infusion of the liquid formulation into the skin of a patient at a relatively low pressure, for example, by capillary action. Infusing a liquid formulation into a large area of patient skin may include infusing the liquid formulation through at least a majority of the microneedles of the microneedle array. That is, the number of participating microneedles may be increased to provide a larger liquid formulation administration area at low pressure.

The foregoing presents a simplified summary of some aspects of the disclosure in order to provide a basic understanding. The foregoing summary is not intended to be broad and is not intended to identify key or critical elements of the invention or to delineate the scope of the invention. The purpose of the foregoing summary is to present some concepts of the disclosure in a simplified form as a prelude to the more detailed description that is presented later. Other aspects will become apparent from the following, for example.

Drawings

In the following, reference is made to the accompanying drawings, which are not necessarily drawn to scale and which may be schematic. The drawings are exemplary only, and should not be construed as limiting the invention.

Fig. 1 is a cross-sectional view of a drug delivery device according to a first embodiment herein.

Fig. 2 is a detailed view of a portion of the device shown in fig. 1.

Fig. 3 is a more detailed schematic cross-sectional view of a portion of the microneedle array assembly shown in fig. 2.

Fig. 4 shows an arrangement pattern of a microneedle array without a uniformity control film as a comparative example.

Fig. 5 is a diagrammatic illustration of a portion of a microneedle array assembly according to a second embodiment herein.

FIG. 6 is a graph schematically illustrating how an appropriately configured uniformity control membrane seeks to advantageously reduce the effects of variations in froth pressure associated with microneedles of a microneedle array in accordance with a second embodiment.

Detailed Description

Exemplary embodiments are described below and illustrated in the accompanying drawings, wherein like reference numerals refer to the like elements throughout the several views. The described embodiments provide examples and should not be construed as limiting the scope of the invention. Other embodiments, as well as modifications and improvements to the described embodiments will occur to persons skilled in the art and all such other embodiments, modifications and improvements are within the scope of the present invention.

In the following, a very brief and general initial discussion of the drug delivery device 10 of the first embodiment is followed by a more detailed discussion, e.g. of some of the individual sub-components of the device 10. Discussion directed primarily to structural features of the device 10 is followed more particularly to a discussion of the methods herein.

Referring to fig. 1, device 10 is shown in a partially activated configuration. The device 10 may be characterized as including a plurality of primary sub-assemblies, each of which may be independent. The primary subassembly may include a container 13, a cartridge 16 or other suitable container or reservoir for removable mounting in the container 13, and a mechanical controller 19 mounted to the cartridge 16.

The controller 19 may include a plunger 22, with or without an internal force provider 25 for the plunger 22. The controller 19 is used to apply pressure to the reservoir or cartridge 16 to facilitate expulsion of the liquid drug formulation or any other suitable liquid formulation from the cartridge 16 to the microneedle array 28.

The container 13 of the first embodiment includes a microneedle array 28. Microneedle array 28 includes a plurality of microneedles 31 (fig. 2) for penetrating the skin of a user, such as for providing a fluid in the form of a liquid drug formulation into the skin of a user. The microneedle array 28 may be more generally referred to as a device for engaging the skin of a patient or other user and dispensing a liquid formulation to the skin of the user, such as by dispensing the liquid formulation into an epidermal portion of the skin of the user. In contrast to the manner in which device 10 is shown in fig. 1, at least a portion of microneedles 31 of microneedle array 28 typically protrude outwardly through a lower opening of container 13. Examples of the apparatus 10 are further described in U.S. provisional patent application nos. 61/996,149, 61/996,156, 61/996,157, and 61/996,158, each of which is incorporated by reference herein in its entirety.

As an example, microneedle array 28 can be configured as disclosed in one or more of WO2012/020332 for Ross, WO20111070457 for Ross, WO2011/135532 for Ross, US2011/0270221 for Ross, US2013/0165861 for Ross, and U.S. provisional patent application No. 61/996,148, each of which is incorporated herein by reference in its entirety. In general, the microneedle array 28 of the device 10 may have any suitable configuration known in the art for delivering a liquid formulation onto, into and/or through the skin of a user, such as by being configured to include a plurality of microneedles 31 extending outwardly from a suitable base or support, which may be referred to as a base or floor 34. As shown in fig. 3, the base plate 34 has a top surface 37 (e.g., an upstream side) and a bottom surface 40 (e.g., a downstream side), and the plurality of microneedles 31 extend outwardly from the bottom surface. The base plate 34 and microneedles 31 may generally be constructed from a sheet of rigid, semi-rigid, or flexible material, such as a metallic material, a ceramic material, a polymeric (e.g., plastic) material, and/or any other suitable material. For example, the base plate 34 and the microneedles 31 may be formed of silicon by reactive ion etching or in any other suitable manner.

The bottom plate 34 generally defines a plurality of channels, which may be referred to as holes or openings 43, that extend between the top and

bottom surfaces

37, 40 to allow the liquid formulation to flow therebetween. For example, a single opening 43 may be defined in the base plate 34 adjacent to each microneedle 31. However, in other embodiments, the baseplate 34 may define any other suitable number of openings 43 positioned at the location of each microneedle 31 and/or spaced apart from the location of each microneedle 31. In the first embodiment, each opening 43 leads to or includes a pair of downstream openings or outlets 46, the downstream openings or outlets 46 opening into an outer channel 49, the outer channel 49 being defined in and extending along each microneedle 31. Alternatively, each opening 43 may extend through the floor 34 and through the microneedles 31, as will be discussed in more detail below.

Each microneedle 31 of the microneedle array 28 can include a base that extends downward from the bottom surface 40 and transitions into a piercing shape or needle shape (e.g., a conical or pyramidal shape or a cylindrical transition to a conical or pyramidal shape) having a tip 52 distal from the bottom surface 40. The tip 52 of each microneedle 31 is disposed furthest from the base plate 34 and may define a minimum dimension (e.g., diameter or cross-sectional width) of each microneedle 31. In addition, each microneedle 31 may generally define any suitable length L between its base and its tip sufficient to allow the microneedle 31 to penetrate the stratum corneum and into the epidermis of the user. It may be desirable to limit the length of the microneedles 31 so that they do not penetrate the inner surface of the epidermis and enter the dermis, which may advantageously help to minimize pain for a patient receiving the liquid formulation.

The length L of each microneedle 31 may be less than about 1000 micrometers (μm), such as less than about 800 micrometers, or less than about 750 micrometers, or less than about 500 micrometers (e.g., ranging from about 200 micrometers to about 400 micrometers in length), or any other subrange therebetween. In one particular example, the microneedles 31 may have a length L of about 290 μm. The length of the microneedles 31 may vary depending on the location of use of the device 10 on the user. For example, the microneedles 31 of the device 10 for use on a user's leg may be of a length significantly different from the microneedles of the device 10 for use on a user's arm. Each microneedle 31 may generally define any suitable aspect ratio (i.e., the ratio of the length L to the cross-sectional width dimension W of each microneedle 31). The aspect ratio may be greater than 2, for example greater than 3 or greater than 4. In the case where the ratio of the cross-sectional width dimension (e.g., diameter) to the length of each microneedle 31 varies, the aspect ratio may be determined based on the average cross-sectional width dimension.

Each microneedle 31 may define one or more external channels 49 in fluid communication with the opening 43 defined in the base plate 34. In general, the outer channel 49 may define any suitable location on each microneedle 31. For example, as shown in fig. 3, an external channel 49 may be defined along an outer surface of each microneedle 31. As a more specific example, each external channel 49 may be an outwardly opening groove defined by an outer surface of microneedle 31 and extending along a length of microneedle 31. Alternatively and/or additionally, the channel 49 may be defined by the interior of the microneedles 31 such that each microneedle forms a hollow shaft, in which case the opening 43 and the internal channel may have the same diameter and be coaxial, as discussed in more detail below. Regardless, the combination of the opening 43 and the external passage 49 may generally be configured to form a downstream path that enables the liquid formulation to flow from the top surface 37 of the bottom plate 34, through the opening 43, and into the passage 49, where the liquid formulation may be delivered onto, into, and/or through the skin of the user. The outer channel 49 may be configured to define any suitable cross-sectional shape. For example, each outer channel 49 may define a semi-circular or circular shape. Alternatively, each outer channel 49 may define a non-circular shape, such as a "v" shape or any other suitable cross-sectional shape.

The dimensions of the external channel 49 defined by the microneedles 31 may be specifically selected to induce capillary flow of the liquid formulation. Capillary pressure within the outer channel 49 is inversely proportional to the cross-sectional dimension of the outer channel and proportional to the product of the surface energy of the target liquid times the cosine of the liquid contact angle at the interface defined between the liquid and the outer channel. Thus, to facilitate capillary flow of the liquid formulation through the microneedle array 28, the cross-sectional width dimension of the external channel 49 (e.g., the diameter of the external channel) can be selectively controlled, with smaller dimensions generally resulting in higher capillary pressures. For example, the cross-sectional width dimension of the outer channels 49 may be selected such that the cross-sectional area of each outer channel is from about 1,000 square microns (μm) for the width of each outer channel 49²) To about 125,000 μm²Within a range of, for example, from about 1, 250 μm²To about 60,000 μm²Or from about 6,000 μm²To about 20,000 μm²Or any other subrange therebetween.

Microneedle array 28 may generally include any suitable number of microneedles 31 extending from a base 34 thereof. For example, the actual number of microneedles 31 included in the microneedle array 28 can be from about 10 microneedles per square centimeter (cm)²) To about 1,500 microneedles per square centimeter, e.g., from about 50 microneedles per cm²To about 1250 microneedles/cm²Or from about 100 microneedles/cm²To about 500 microneedles/cm²Or any other subrange therebetween. Microneedles 31 may generally be arranged on the base plate 34 in a variety of different patterns, and such patterns may be designed for any particular use. For example, in some embodiments, the microneedles 31 may be spaced in a uniform manner, such as in the form of a rectangular or square grid or concentric circles. In such embodiments, the spacing of microneedles 31 may generally depend on a number of factors including, but not limited to, the length and width of the microneedles 31, as well as the amount and type of liquid formulation intended for delivery by the microneedles 31 or along the microneedles 31.

As best understood with reference to fig. 2, at least a portion of the floor 34 of the microneedle array can have a substantially rectangular periphery in the form of a peripheral outer channel 55 or include an outer channel 55 that opens downwardly (in view of the individual floors) and can have an overall substantially rectangular shape or any other suitable shape of periphery. In the embodiment shown in fig. 2, the microneedle array 28 is mounted to a backing structure 58 having inner and

outer channels

61, 64 that (considering the backing structure alone) are downwardly open and may have an overall substantially rectangular shape or any other suitable shape.

A substantially rectangular pad 67 may be securely engaged within the outer channel 61 of the interior of the backing structure and securely engage the edges of at least one uniformity control film 70 that engages and covers the top surface 37 of the microneedle array 28. These secure engagements associated with the pad 67 may be created, at least in part, by a frame 73 that is fixedly mounted between the outer channel 55 of the periphery of the microneedle array 28 and the outer channel 64 of the exterior of the backing structure 58. The frame 73 may be mounted between the peripheral outer channel and the outer channel by one or more mechanical connections (e.g., an interference fit and/or any other suitable fastening technique). In a first embodiment, the microneedle array 28 is substantially fixedly attached to the backing structure 58 of the support assembly of the container 14 by a body attachment.

Frame 73 may be characterized as a substantially rectangular perimeter frame having a generally S-shaped cross-section. The outer periphery of the frame 73 may be press fit into the outer channel 64 such that the outer periphery of the frame 73 is in compressed, face-to-face contact with a flange 76 that is part of or otherwise associated with (e.g., partially defined by) the outer channel 64 and the inner periphery of the frame 73 is in compressed, face-to-face contact with the bottom surface 40 of the bottom plate 34. More specifically, frame 73 engages the surface of outer channel 55 at the periphery of base plate 34.

Referring back to fig. 1, the container 13 also includes at least one sleeve 79 fixedly mounted on the backing structure 58 for movement therewith. For example, the lower portion of the sleeve 79 may be fixedly mounted in a supply port extending through the backing structure 58 by one or more mechanical connections, such as an interference fit, an adhesive material, and/or any other suitable fastening technique. The lower open end of the sleeve 79 is in fluid communication with the upstream side of the uniformity control membrane 70 (fig. 2), and the upper open end (typically sharp) of the sleeve 79 extends axially upward from the backing structure 58 for piercing a predetermined portion of the cartridge 16 to access the reservoir 80 therein.

The combination of at least the microneedle array 28 and the uniformity control membrane 70 may be referred to herein as a microneedle array assembly 71. At least the backing structure 58 is cooperatively configured with the microneedle array assembly 71 such that a peripherally enclosed plenum 82 (fig. 3) is defined therebetween. The plenum 82 is preferably hermetically sealed or closed except for an aperture 85 (fig. 3) that opens to a supply port (e.g., provided by a sleeve 79 extending through the backing structure 58) and opens to the uniformity control membrane 70.

During operation of the device 10 after being configured substantially as shown in fig. 1, the plunger 22 applies pressure to the cartridge 16 and liquid formulation flows through the cannula 79 into the pumping chamber 82. The liquid formulation exits the plenum 82 by flowing through the apertures 85 of the uniformity control membrane 70 and then flows through the openings 43 in the base plate 34 to the outer channels 49 associated with the microneedles 31 and into the skin of the user.

Restated from the above and as shown in fig. 3, the top surface 37 of the base plate 34 of the microneedle array 28 is covered with one or more uniformity control films 70 to at least partially form a microneedle array assembly 71. The uniformity controlling membrane 70 may be made of a permeable, semi-permeable, or microporous material configured to cause a pressure drop as the liquid formulation flows therethrough. In one example, a suitable pressure drop across the uniformity controlling membrane 70 may be from 0.25 kilopascals (kPa) to 50kPa, from 10kPa to 10kPa, from 2.0 to 5.0kPa, from about 0.25kPa to about 50kPa, from about 10kPa to about 10kPa, from about 2.0 to about 5.0kPa, or any other subrange therebetween, at a predetermined flow rate of a predetermined pharmaceutical formulation.

The uniformity control film 70 can be schematically modeled as having a number of discrete apertures 85 to allow the liquid formulation to flow from the plenum 82 (on the upstream side of the uniformity control film) to the apertures 43 (on the downstream side of the uniformity control film). In the first embodiment, the total area of the holes 85 is smaller than the total area of the openings 43.

The uniformity control film 70 may be a track etch film. The track etched membrane provides an advantage in that the liquid formulation is generally restricted to flow through the thickness of the uniformity control membrane 70 from side to side, substantially preventing diffusion of the liquid formulation within the uniformity control membrane in a lateral direction perpendicular to the thickness of the uniformity control membrane. Suitable track etched membranes are available from Sterlitech corporation of kente washington, usa and may be in the form of 0.05 micron hydrophilic polycarbonate track etched membranes or the like.

In the first embodiment, a uniformity control film 70 is associated with the top surface 37 of the backing structure 34 to limit or prevent lateral movement of the liquid formulation between the uniformity control film 70 and the base plate 34. In other words, liquid formulation associated with (e.g., adjacent to) one opening 43 should generally be prevented from traveling over the top surface 37 into an adjacent opening 43. When the uniformity control film 70 is a track-etched film, it may have a smooth side and a rough side. Generally, it is preferred to have a smooth surface against the top surface 37 to avoid unwanted lateral flow of the liquid formulation.

The uniformity control membrane 70 is held tightly against the top surface 37 of the base plate 34 by the pressure applied by the frame 73 and the gasket 67 around the periphery of the uniformity control membrane 70. During operation of the device 10, the liquid pressure of the drug formulation within the pumping chamber 82 may be sufficient to maintain the central region of the uniformity control membrane 70 on the top surface 37.

Referring back to fig. 1, during operation of the device 10, the plunger 22 and the internal force provider 25 of the controller 19 may force the liquid formulation out of the cartridge 16 such that the liquid formulation substantially uniformly fills the pumping chamber 82 (fig. 3) and substantially uniformly wets the uniformity control membrane 70. In other words and referring to fig. 3, a liquid formulation may generally be used for each opening 43 at the top surface 37 of the bottom plate 34. Referring to fig. 1, the internal force provider 25 (e.g., at least one spring) acts in conjunction with the plunger 22 to substantially completely evacuate the cartridge 16 of liquid formulation through the cannula 79 and into the plenum 82. The plunger 22 and internal force provider may provide a force in the range of 1.1 newtons (N) to 1.3N, about 1.1N to about 1.3N, 2N to 2.2N, about 2N to about 2.2N, 2.4N to 2.6N, about 2.4N to about 2.6N, 2.7N to 2.9N, about 2.7N to about 2.9N, or any other subrange therebetween. The device 10 shown in fig. 1 is provided as an example only. That is, the microneedle array assembly 71 may be used with or otherwise incorporated into any other suitable device. For example, the plunger 22, the force provider 25, and/or the controller 19 may be replaced with other suitable components to force the liquid formulation into the pumping chamber 82, etc.

The uniformity control membrane 70 may be selected such that the pressure drop created by the flow of the liquid formulation through the uniformity control membrane consumes substantially all of the pressure energy imparted to the liquid formulation by the plunger 22 and the internal force provider 25. For example, the pressure increase provided by the plunger 22 and the internal force provider 25 may have an absolute value that is approximately equal to the absolute value of the pressure decrease provided by the uniformity control membrane 70. According to the method of operation of the first embodiment, the pressure immediately downstream of the uniformity control membrane 70 may only be sufficient to cause or allow the liquid formulation to reach the channel 49 in a manner such that there is capillary flow of the liquid formulation in the outer channel 49 of the microneedles 31.

Several variables should be considered together to produce the capillary flow that may be desired. For example, the greater the force exerted by plunger 22, the higher the pressure through cannula 79 and the higher the pressure of the liquid formulation within pumping chamber 82. To maintain the target flow rate, the uniformity control membrane 70 should be able to increase the pressure drop to equalize the increased pressure within the plenum 82. As a result, the uniformity control membrane 70 generally has a flow resistance selected in association with the plenum pressure and the subsystem comprising the plunger 22 and the force provider 25 (if present).

As can be best understood with further regard to the microneedle array assembly 71 of the first embodiment and with reference to fig. 3, the microneedle array assembly has a number of combined flow paths extending through the microneedle array assembly, and each combined flow path may be characterized as including an upstream flow path and at least one downstream flow path. For each combined flow path extending through the microneedle array package 71, the upstream flow path may be comprised of one or more corresponding apertures 85 of the uniformity control membrane 70, such that each upstream flow path may be designated by the reference numeral 85. For each combined flow path extending through the microneedle array package 71, at least one downstream flow path may include, consist essentially of, or consist of a respective opening 43 and a respective one or more outlets or downstream openings 46, such that for the sake of brevity, each downstream flow path may be designated with

reference numerals

43, 46 or with reference numeral 43 alone. At least in theory, for each or most of the combined flow paths of the first embodiment, the downstream end of the upstream flow path 85 communicates directly with the upstream end of the respective downstream flow path 43 to prevent lateral bypass flow, generally as described above.

As a first comparative example, fig. 4 shows the downstream side of the microneedle array 28, where the uniformity control membrane 70 is not associated with the upstream side of the microneedle array, and the downstream side of the microneedle array discharges water at a relatively low pressure and at a rate of about 200 microliters per hour (μ l/hr), for example, by capillary action. As shown in fig. 4, with the first comparative example, even if water is uniformly applied to the entire upstream side of the microneedle array 28, the water flows through the microneedle array only at a small number of discrete locations, so that most of the area of the microneedle array remains dry on the downstream side thereof. That is, fig. 4 shows water being discharged from a relatively small percentage of the downstream flow paths 43, so that the number of participating flow paths 43 is relatively small. This indicates that, for the first comparative example, the flow-through microneedle array 28 significantly lacks drainage uniformity and the efficacy of the large area application site of the microneedle array is greatly reduced.

Manufacturing techniques typically limit the ability to form downstream openings of the downstream flow path 43 having exactly the same diameter or cross-sectional area, which in some cases may result in significant discharge uniformity deficiencies, such as the discharge uniformity deficiency shown in fig. 4. More specifically, with respect to the fact that manufacturing techniques may limit the ability to form downstream openings of downstream flow paths 43 having substantially the same diameter or cross-sectional area, foam of liquid formulation exiting from relatively large downstream flow paths 43 will have a larger foam radius, and correspondingly a smaller surface tension, than foam of liquid formulation exiting from relatively small downstream flow paths 43. The energy required to add more liquid formulation to the larger foam is less than the energy required to add liquid formulation to the smaller foam that is pushed out of the smaller downstream flow path 43. In the first comparative example discussed above with reference to fig. 4, the large foam will increase slightly and the pressure in the foam will decrease further. The result is that liquid formulation can flow through one or more of the larger downstream flow paths 43 without flowing through the smaller downstream flow paths, even if the smaller downstream flow paths adequately contain liquid formulation.

According to a first embodiment (as opposed to the comparative example of fig. 4, for example), the uniformity control film 70 may be adapted in a manner that seeks to increase the uniformity of the discharge across the microneedle array 28. For example, at least the uniformity controlling membrane 70 and the microneedle array 28 are cooperatively configured in a manner that seeks to allow substantially uniform infusion of the liquid formulation over a large area, such as by capillary action, and at a relatively low pressure, wherein substantially uniform infusion of the liquid formulation over the large area includes steady flow of the liquid formulation through a relatively large percentage of the downstream flow paths 43 and away therefrom, such that the number of participating downstream flow paths is relatively large. That is, by increasing the number of participating downstream flow paths 43 while maintaining a substantially similar target flow rate and relatively low administration pressure, the uniformity control membrane 70 may be configured to provide improved efficacy for the useful area of the microneedle array 28 relative to the first comparative example.

For each participating downstream flow path 43, the liquid formulation may flow stably through and out of the flow path. That is, the participating downstream flow path 43 through the microneedle array 28 is a downstream flow path having the liquid formulation flowing therethrough and out therefrom. Increasing the number of participating downstream flow paths 43 means increasing the percentage of downstream flow paths from which the liquid formulation flows out at a predetermined target flow rate and pressure. By increasing the number of participating downstream flow paths 43, it is believed that the infusion of the liquid formulation is more uniform over the entire area of the microneedle array 28. Because the body's response to the drug is region-dependent, increasing the uniformity of expulsion from microneedle array 28 can improve the effectiveness of the drug formulation on the body.

The use of a uniformity control membrane 70 as described herein provides an unexpected and critical improvement in the number of participating downstream flow paths 43 having a predetermined target flow rate and pressure for the microneedle array 28. In this regard, the resistance to flow through the uniformity control membrane 70 is at least about 30 times, at least about 40 times, at least about 50 times, between about 30 times and about 100 times, between about 40 times and about 100 times, or between about 50 times and about 100 times the resistance to flow through the microneedle array 28. These flow resistances and associated flow paths are discussed in more detail below, sometimes with reference to the first, second, first and second comparative examples herein.

The second embodiment herein may be similar to the first embodiment except for the variations indicated and obvious to those of ordinary skill in the art. Thus, reference numerals for features of the second embodiment that at least generally correspond to features of the first embodiment have been increased by one hundred.

As schematically shown in fig. 5 for the second embodiment, each downstream flow path 143 of the microneedle array 128 may alternatively or alternatively be in the form of an internal channel extending through the interior of the microneedles 131 such that each microneedle forms a hollow shaft. That is, each downstream flow path 143 of the second embodiment may include an internal passage, and for example, the external passage 49 of the first embodiment may be omitted.

As an example, when the microneedle array assembly 171 is in use and the liquid formulation flows through the upstream flow path 185 and reaches the upstream opening of the downstream flow path 143, the liquid formulation will attempt to enter the upstream opening of the downstream flow path 143. For example, when the liquid formulation forms a contact angle with the downstream flow path 143 that is less than 90 degrees (e.g., when the adhesive force is stronger than the cohesive force), the downstream flow path 143 may fill the downstream opening of the downstream flow path due to capillary action. At this time, the downstream opening of each downstream flow path 143 may be summarized as having an independent boundary between the liquid formulation and the air. The boundary between a liquid (e.g., a liquid drug formulation) and a gas (e.g., air) has a surface tension. When the boundary between the liquid and the gas is deformed, the surface tension changes due to the change in curvature of the surface formed at the boundary. As the liquid formulation is pushed outward from the downstream openings of the downstream flow path 143, the liquid formulation is pushed into the air, and droplets or bubbles of the liquid formulation may exit each downstream opening of the downstream flow path. The curvature of these bubbles is first small and increases as the liquid formulation flows through the downstream flow path 143. However, as described above, one outlet of the liquid formulation may be frothed larger than the other in some instances, for example, due to a change in size of the downstream opening of the downstream flow path 143, or for one or more other reasons.

Some aspects of the factors associated with the flow of the liquid formulation and associated foam may be understood with reference to the theoretical system of fig. 5 and the equations and calculations given below. Plenum 182 and upstream and

downstream flow paths

185, 143 are filled with fluid and there is a fluid/air interface at the downstream opening of the downstream flow path for purposes of the following equations and calculations. The flow through the first downstream flow path 143 is Q₁And the flow through the second downstream flow path 143 is Q₂。R₁Representing any flow resistance immediately upstream at the upstream opening of the upstream flow path 185. R₂And R₄Is the resistance to flow through the uniformity control film 170 or, more specifically, through the upstream flow path 185. R₃Is the resistance to flow through the first downstream flow path 143, R₅Is the resistance to flow through the second downstream flow path 143. P_inIs the pressure of the source. P₁And P₄Respectively, the pressure at the upstream opening of the upstream flow path 185. P₂And P₅Respectively, the pressure at the upstream opening of the downstream flow path 143. P₃And P₆Respectively, the pressure at the downstream opening of the downstream flow path 143.

Pressures P at a plurality of downstream openings of the downstream flow path 143, respectively₃And P₆And is typically neither constant nor zero. More specifically, these pressures P₃And P₆Respectively, depending on the shape of the fluid exiting the downstream opening of the downstream flow path 143. In one example, the pressure P at the plurality of downstream openings of the downstream flow path 143₃And P₆(e.g., foam pressure) may all be about 1200 pascals (Pa), as indicated by the TableThe pressure required to push the fluid out of the downstream opening of each downstream flow path and into the air is shown.

Pressures P at a plurality of downstream openings of the downstream flow path 143, respectively₃And P₆Can be calculated by the young-laplace equation, which relates surface tension at the fluid/gas interface, fluid curvature and pressure drop, as follows:

in the above-mentioned Young-Laplace equation, r₁And r₂Is the primary radius of curvature of the foam of the liquid formulation exiting the downstream opening of the downstream flow path 143. The radius of curvature varies with the amount of fluid flowing. At low amounts, the curvature is small and the pressure is large. As the fluid flows, the radius increases and the pressure decreases.

The pressure reduction mentioned in the previous sentence may cause problems when trying to infuse liquid preparations at relatively low pressures. For example, where the downstream opening of the first downstream flow path 143 is slightly larger than the downstream opening of the second downstream flow path, the foam pressure at the downstream opening of the first downstream flow path may be slightly smaller than the foam pressure at the downstream opening of the second downstream flow path, such that the upstream liquid formulation may preferentially flow into the first downstream flow path. As a result, a large foam of the liquid formulation at the downstream opening of the first downstream flow path 143 may be changed to be large, and a small foam of the liquid formulation at the downstream opening of the second downstream flow path may be changed to be small, so that the liquid formulation may flow through the first downstream flow path instead of the second downstream flow path. That is, as described above, the difference in the bubble pressure may cause the uniformity of the flow in the microneedle array 128 to be low.

According to one aspect of the invention, the

uniformity control membrane

70, 170 may be configured in a manner that seeks to reduce the effects of foam pressure differences to optimize the number of

downstream flow paths

43, 143 participating at a predetermined target flow rate and pressure. For example, the

uniformity control membrane

70, 170 may be advantageously configured to attempt to inhibit the pressure at the upstream opening of the

downstream flow path

43, 143 from substantially dropping significantly in response to flow through an adjacent downstream flow path such that flow through the adjacent downstream flow path does not adversely affect flow through the other downstream flow path. This relationship between a pair of adjacent

downstream flow paths

43, 143 can generally be understood with reference to the equations discussed below.

For the theoretical system of fig. 5, the flow into the system is the sum of the flows through the first and second downstream flow paths 143, as shown by the following equation:

Q_in＝Q₁+Q₂equation 2

Flow is proportional to pressure drop and inversely proportional to resistance. Thus, the flow rate through the first downstream flow path 143 can be determined by the following equation:

similarly, the flow rate flowing through the second downstream flow path 43 may be determined by the following equation:

from the foregoing equations, a system of equations relating pressure drop, resistance and flow rate can be generated and solved. For example, the following table represents values associated with a second comparative example based on FIG. 5, but does not actually include any uniformity control

According to the first and second embodiments, the

uniformity control membrane

70, 170 may be configured in a manner that seeks to cause the pressure at the upstream opening of one

downstream flow path

43, 143 not to change significantly in response to flow through an adjacent downstream flow path. In this regard, from the above equation, the method for determining P can be derived₂And as follows:

to determine P₂With P₆How the change of (2) changes can be determined by assuming R₁Equal to zero, R₂And R₄Are equal to each other, and R₃And R₅Are equal to each other, and P₆And P₃The difference between can be expressed in β to simplify the above equation to yield the following simplified equation:

from the simplified equations above, a system of equations can be generated and solved for the calculated P₂Resistance (i.e., R) to the uniformity control film 170₂) And the pressure deviation (i.e., β) between adjacent downstream openings of the downstream flow path 143. For example, 0.027um can be used³Q of/s_in(i.e., 100ul/hr), 1200Pa of P₃And 10,000Pa s/um³R of (A) to (B)₃To solve equation 6, wherein the calculated relationship is shown in FIG. 6, wherein the vertical axis (i.e., z-axis) represents P₂。

FIG. 6 schematically illustrates how a properly configured

uniformity control membrane

70, 170 can help advantageously reduce the bubble pressure (e.g., β, or more specifically, P) at the downstream opening of the plurality of downstream flow paths 143₃And P₆Change in between) of the change. For example and referring to the system of FIG. 5 and equation 6, P₂As the foam pressure (e.g., P) at the adjacent downstream opening of the downstream flow path 143₃And P₆Change in β) can be represented by the following equation:

the above equation provides how a properly configured

uniformity control film

70, 170 can help advantageously reduce the bubble pressure (e.g., β, or more specifically, P) at the downstream opening of the different downstream flow paths 143₃And P₆Change between) change. For example, if the foam pressure (e.g., β, or more specifically, P) at the downstream opening of the downstream flow path 143₃And P₆Change in between) up to 1200Pa and the desired pressure P₂If the deviation is less than 1%, equation 7 can be expressed as follows:

equation 8 may be expressed as follows for determining R₃R is greater than R should be₂Or more generally, the resistance to flow through the

uniformity control membrane

70, 170 should be somewhat greater than the resistance to flow through the

microneedle array

28, 128.

Solving equation 9 results in a K of 49; thus, in this example, R₂Should be at least R₃About fifty times, or more generally, the resistance to flow through the

uniformity control membranes

70 and 170 should be at least about fifty times greater than the resistance to flow through the

microneedle arrays

28 and 128, respectively. More generally, the resistance to flow through the

uniformity control membranes

70 and 170 can be at least about 30 times, at least about 40 times, at least about 50 times, between about 30 and about 100 times, between about 40 and 100 times, or between about 50 and 100 times the resistance to flow through the

microneedle arrays

28 and 128, respectively.

As mentioned above with reference to FIG. 5 and according to one example, the pressure P at the downstream opening of each of the plurality of

downstream flow paths

43, 143₃And P₆(e.g., the foam pressure of the fluid formulation) may be about 1200Pa, which may represent the pressure required to push the fluid formulation out of the downstream opening of the downstream flow path and into the air. At the operation sideIn examples of methods, the pressure drop across the

uniformity control membranes

70 and 170 can be at least about 30 times, at least about 40 times, at least about 50 times, between about 30 times and about 100 times, between about 40 times and 100 times, or between about 50 times and 100 times the pressure required to push the fluid formulation out of the downstream opening of the

downstream flow path

43, 143 and into the air. The pressure required to push the fluid formulation out of the downstream opening of the

downstream flow path

43, 143 and into the air may be generally referred to as the foam pressure of the

microneedle arrays

28 and 128. Thus, the pressure drop across the

uniformity films

70 and 170 may be at least about 30 times, at least about 40 times, at least about 50 times, between about 30 and about 100 times, between about 40 and 100 times, or between about 50 and 100 times the bubble pressure of the

microneedle arrays

28 and 128, respectively.

As described above, for each combined flow path extending through the

microneedle array assembly

71, 171, the downstream opening of the

upstream flow path

85, 185 may be in direct communication with the upstream opening of the

downstream flow path

43, 143, for example, due to the

uniformity control film

70, 170 securely engaging the upstream side of the

microneedle array

28, 128. According to one aspect herein and reiterated at least in part from above, the resistance to flow through the

upstream flow path

85, 185 can be significantly higher than the resistance to flow through the

downstream flow path

43, 143, with these differences in flow resistance attempting to facilitate uniform infusion of the liquid formulation, e.g., by capillary action, into the skin of a patient, e.g., at relatively low pressures over large areas. Infusing a liquid formulation into the skin of a patient over a large area may include infusing the liquid formulation through at least a majority of the

downstream flow path

43, 143 such that the liquid formulation is infused through at least a majority of the microneedles of the

microneedle arrays

28, 128.

That is, the

uniformity control membrane

70, 170 may have the effect of significantly increasing the total resistance to flow through each combined flow path (e.g.,

upstream flow path

85, 185 and downstream flow path 43, 443) in a manner that minimizes the difference in total flow resistance in the plurality of combined flow paths. As a result, when the liquid formulation is infused at a low pressure, e.g., a sufficiently low pressure, the liquid formulation can actively utilize (i.e., flow through) an increased number of the combined flow paths such that a majority of the liquid formulation is administered by capillary action. That is, the number of participating combined flow paths can be increased to provide a larger liquid formulation administration area at low pressure. The liquid formulation infused through at least a majority of the

downstream flow path

43, 143 may comprise liquid formulation infused through at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the

downstream flow path

43, 143.

In one aspect of the present invention, when liquid formulation is initially supplied to the upstream opening of the

upstream flow path

85, 185 and fills the combined flow path, outwardly bulging bubbles of liquid formulation may form at the downstream opening of the

downstream flow path

43, 143, and these bubbles contribute to the resistance to flow through the

downstream flow path

43, 143. In one example, the foam of the liquid formulation may be a bead of the liquid formulation in ambient air or the outside world or the like (e.g., a thin layer of air covering a portion of the patient's skin where the liquid formulation is to be infused). Further, with respect to the outwardly projecting foam of the liquid formulation initially formed at the downstream openings of the

downstream flow paths

43, 143, relatively small foam may be formed at some downstream openings, and relatively large foam may be formed at another downstream opening. The pressure of the liquid formulation in the relatively small foam is greater than the pressure of the liquid formulation in the relatively large foam, so that the flow resistance due to the small foam is greater than the flow resistance due to the large foam. At least in theory, the resistance to flow through the

uniformity control membrane

70, 170 may be sufficiently large that the pressure drop through the

upstream flow path

85, 185 of the combined flow path having relatively large and expanding bubbles may exceed the pressure drop in the upstream portion of the combined flow path having relatively small bubbles. In this regard, the pressure drop in the upstream portion of the combined flow path having the relatively large and expanding foam may exceed any pressure drop in the upstream portion of the combined flow path having the relatively small foam in a manner that substantially equalizes flow through the combined flow path such that a majority of the foam formed at the downstream opening of the downstream portion of the combined flow path is broken and replaced by the increasingly outward flowing liquid formulation stream.

The above embodiments are in no way intended to limit the scope of the present invention. Those skilled in the art will appreciate that while the present disclosure has been discussed above with reference to exemplary embodiments, various additions, modifications and changes may be made thereto without departing from the spirit and scope of the present disclosure, some of which are set forth in the following claims.

Claims

1. A microneedle array package comprising:

a microneedle array comprising

A base having opposite upstream and downstream sides and defining a plurality of openings extending between the upstream and downstream sides, an

A plurality of microneedles extending from the downstream side, and

at least one membrane joined to an upstream side of the base,

wherein the microneedle array is cooperatively configured with the at least one membrane such that a plurality of flow paths extend through the microneedle array assembly and a resistance to flow through the at least one membrane on an upstream side of the base is at least 30 times greater than a resistance to flow through the microneedle array, wherein at least 30 times is a difference in flow resistance between the upstream and downstream sides of the base, and wherein the difference is measured at a plurality of openings of the base.

2. The microneedle array package of claim 1, wherein the resistance to flow through the at least one membrane is 30 to 100 times greater than the resistance to flow through the microneedle array.

3. The microneedle array package of claim 1, wherein a resistance to flow through the at least one membrane is at least 40 times greater than a resistance to flow through the microneedle array.

4. The microneedle array package of claim 3, wherein the resistance to flow through the at least one membrane is 40 to 100 times greater than the resistance to flow through the microneedle array.

5. The microneedle array package of claim 1, wherein a resistance to flow through the at least one membrane is at least 50 times greater than a resistance to flow through the microneedle array.

6. The microneedle array package of claim 5, wherein the resistance to flow through the at least one membrane is 50 to 100 times greater than the resistance to flow through the microneedle array.

7. The microneedle array package of claim 1, wherein the at least one membrane being engaged with the upstream side of the base comprises a downstream side of the at least one membrane being engaged with the upstream side of the base in a manner that restricts any flow between a plurality of flow paths extending through the microneedle array package at an interface between the downstream side of the at least one membrane and the upstream side of the base.

8. The microneedle array package of claim 1, wherein the at least one membrane has a relatively smooth side and a relatively rough side, and engaging the at least one membrane with the upstream side of the base comprises engaging the smooth side of the at least one membrane with the upstream side of the base.

9. The microneedle array package of claim 1, wherein the at least one membrane is a track etched membrane.

10. A drug delivery device comprising:

a microneedle array package according to claim 1; and

a reservoir operably associated with the microneedle array for supplying liquid to the microneedle array through the at least one membrane.

11. The drug delivery device of claim 10, further comprising a force provider for flowing at least some liquid from the reservoir to the microneedle array assembly.

12. The drug delivery device of claim 11, wherein:

the force provider is used for causing the pressure of the liquid to rise;

the at least one membrane is used to cause a reduction in the pressure of the liquid; and is

The absolute value of the pressure increase is substantially equal to the absolute value of the pressure decrease.

13. The drug delivery device of claim 11, further comprising a plenum in fluid communication with an upstream side of the plenum, wherein the force provider is for flowing at least some liquid from the reservoir to the plenum.

14. The drug delivery device of claim 13, further comprising a cannula in fluid communication with the plenum chamber, wherein the drug delivery device is configured such that, in use, liquid enters the plenum chamber from the reservoir through the cannula before flowing through the at least one membrane and out of the microneedle array.